Abstract 311: Optimization of treatment schedule for the combination therapy of ATR inhibitor elimusertib and PARP inhibitor niraparib in preclinical tumor models
Authors: Antje Margret Wengner, Gerhard Siemeister, Bart Ploeger, Lisa Ehresmann, Nils Guthof, Gary Wilkinson
Journal: Cancer Research (2023)

Abstract Background: Ataxia telangiectasia and Rad3-related (ATR) kinase and poly-(ADP-ribose) polymerase (PARP) are central components of the DNA damage response (DDR) machinery that act via distinct DNA repair pathways whereby combined inhibition of ATR and PARP is expected to be highly synergistic. Elimusertib is a potent and selective ATR inhibitor currently in phase I development in patients with advanced solid tumors carrying DDR defects. Niraparib is an approved PARP inhibitor for the treatment of ovarian cancer. Several different dosing schedules of a combination treatment with elimusertib and niraparib were explored in preclinical tumor model systems to identify a dose regimen that optimally balances safety and efficacy for translation into clinical studies. Methods: Preclinical human mCRPC xenograft model 22RV1 in male immunocompromised (NMRI nude) mice was used. Multiple variations of treatment duration and sequence of drug application were investigated. Both drugs were used at their MTD in the respective combination dosing regimen. Antitumor activity was assessed by tumor area measurement, and safety/tolerability was determined by body weight change and evaluation of hematological parameters. Results: Preclinical data demonstrated strong synergistic antitumor activity resulting from combined blockade of ATR and PARP. In vitro and in vivo data revealed that concomitant inhibition of both ATR and PARP mediated DNA repair is required for maximal synergy. 13 different combination dosing schedules were tested in vivo. Elimusertib was dosed between 20 and 40 mg/kg BID for 3 days on/4 days off, or 3 days on/11 days off. Niraparib was dosed QD continuously or using various intermittent schedules. Overall, best efficacy and tolerability was achieved when PARPi and ATRi were applied concurrently using a discontinuous schedule. The condensed treatment time of both drugs and the extended treatment-free period demonstrated better mitigation of hematological effects, reducing the treatment impact on red blood cell counts in peripheral blood. Conclusion: In preclinical in vitro and in vivo studies it was demonstrated that concurrent inhibition of ATR and PARP resulted in higher tumor cell cytotoxicity than any sequential blockade of ATR and PARP. Evaluating different treatment regimens of combined elimusertib and niraparib indicated that applying both drugs using a discontinuous schedule to balance efficacy and safety in a preclinical mCRPC xenograft model produces an optimal therapeutic window. A non-randomized, open-label trial evaluating the safety and efficacy of elimusertib in combination with niraparib for the treatment of patients with advanced solid tumors is currently ongoing (NCT04267939). Citation Format: Antje Margret Wengner, Gerhard Siemeister, Bart Ploeger, Lisa Ehresmann, Nils Guthof, Gary Wilkinson. Optimization of treatment schedule for the combination therapy of ATR inhibitor elimusertib and PARP inhibitor niraparib in preclinical tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 311.